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Control of immune cell function by the unfolded protein response

Nature Reviews Immunology volume 23, pages 546–562 (2023)Cite this article

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Abstract

Initiating and maintaining optimal immune responses requires high levels of protein synthesis, folding, modification and trafficking in leukocytes, which are processes orchestrated by the endoplasmic reticulum. Importantly, diverse extracellular and intracellular conditions can compromise the protein-handling capacity of this organelle, inducing a state of ‘endoplasmic reticulum stress’ that activates the unfolded protein response (UPR). Emerging evidence shows that physiological or pathological activation of the UPR can have effects on immune cell survival, metabolism, function and fate. In this Review, we discuss the canonical role of the adaptive UPR in immune cells and how dysregulation of this pathway in leukocytes contributes to diverse pathologies such as cancer, autoimmunity and metabolic disorders. Furthermore, we provide an overview as to how pharmacological approaches that modulate the UPR could be harnessed to control or activate immune cell function in disease.

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Fig. 1: Overview of unfolded protein response signalling pathways.
Fig. 2: Intrinsic activation of unfolded protein response sensors during physiological immune responses.
Fig. 3: Pathological unfolded protein response signalling in immune cells in cancer.
Fig. 4: Pathological unfolded protein response signalling in immune cells in metabolic disease.
Fig. 5: Pathological and protective unfolded protein response signalling in immune cells in autoimmune disease and ageing.

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Acknowledgements

P.-C.H. was supported in part by SNSF project grants (31003A_182470), Helmut Horten Stifung, Cancer Research Institute Lloyd J. Old STAR Award and the ERC Starting Grant (802773-MitoGuide). S.C.-C.H. was supported by American Cancer Society Research Scholar Grant (RSG-22-135-01-IBCD), Melanoma Research Foundation Career Development Award, Andrew McDonough B+ Foundation Grant Award, Cancer Research Institute CLIP Investigator Award, VeloSano Pilot Award, Case GI SPORE DRP Grant (5P50CA150964-08) and Case Comprehensive Cancer Center American Cancer Society Pilot Grants (IRG-91-022-19, IRG-16-186-21). J.C.-R. has been supported in part by US Department of Defense Grants OC190443, OC200166 and OC200224; Stand Up to Cancer Grants SU2C-AACR-IRG-03-16 and SU2C-AACR-PS-24; National Institutes of Health Grants R01NS114653 and R21CA248106 and The Mark Foundation for Cancer Research ASPIRE Award.

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Authors and Affiliations

  1. Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland

    Giusy Di Conza & Ping-Chih Ho

  2. Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland

    Giusy Di Conza & Ping-Chih Ho

  3. Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA

    Juan R. Cubillos-Ruiz

  4. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA

    Juan R. Cubillos-Ruiz

  5. Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA

    Juan R. Cubillos-Ruiz

  6. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Stanley Ching-Cheng Huang

  7. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Stanley Ching-Cheng Huang

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  1. Giusy Di Conza
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The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Ping-Chih Ho, Juan R. Cubillos-Ruiz or Stanley Ching-Cheng Huang.

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Competing interests

G.D.C. is employed at iOnctura SA. P.-C.H. serves as a scientific advisor for Elixiron Immunotherapeutics and is a co-founder of Pilatus Biosciences. J.R.C.-R. serves as scientific consultant for NextRNA Therapeutics, Inc., Immagene, B.V. and Autoimmunity Biologic Solutions, Inc. J.R.C.-R. holds patents on the targeting of ER stress responses for the treatment of disease. S.C.-C.H. declares no competing interests.

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Di Conza, G., Ho, PC., Cubillos-Ruiz, J.R. et al. Control of immune cell function by the unfolded protein response. Nat Rev Immunol 23, 546–562 (2023). https://doi.org/10.1038/s41577-023-00838-0

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